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Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a "third factor" would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or - by increasing or decreasing the threshold - can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning.